TY - JOUR AU - Ameratunga, R AU - Koopmans, W AU - Woon, S-T AU - Leung, E AU - Lehnert, K AU - Slade, CA AU - Tempany, JC AU - Enders, A AU - Steele, R AU - Browett, P AU - Hodgkin, PD AU - Bryant, VL Y2 - 2020/12/21 Y1 - 2017/10/20 SN - 2050-0068 UR - http://hdl.handle.net/11343/257600 AB - Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies where monogenetic causes account for only a fraction of cases. On this evidence, CVID is potentially polygenic and epistatic although there are, as yet, no examples to support this hypothesis. We have identified a non-consanguineous family, who carry the C104R (c.310T>C) mutation of the Transmembrane Activator Calcium-modulator and cyclophilin ligand Interactor (TACI, TNFRSF13B) gene. Variants in TNFRSF13B/TACI are identified in up to 10% of CVID patients, and are associated with, but not solely causative of CVID. The proband is heterozygous for the TNFRSF13B/TACI C104R mutation and meets the Ameratunga et al. diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the TNFRSF13B/TACI mutation. Her brother, homozygous for the TNFRSF13B/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole-exome sequencing of the family revealed a de novo nonsense mutation (T168fsX191) in the Transcription Factor 3 (TCF3) gene encoding the E2A transcription factors, present only in the proband and her son. We demonstrate mutations of TNFRSF13B/TACI impair immunoglobulin isotype switching and antibody production predominantly via T-cell-independent signalling, while mutations of TCF3 impair both T-cell-dependent and -independent pathways of B-cell activation and differentiation. We conclude that epistatic interactions between mutations of the TNFRSF13B/TACI and TCF3 signalling networks lead to the severe CVID-like disorder and SLE in the proband. LA - English PB - WILEY T1 - Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency disorder and systemic lupus erythematosus DO - 10.1038/cti.2017.41 IS - Clinical and Translational Immunology VL - 6 IS - 10 L1 - /bitstream/handle/11343/257600/PMC5671988.pdf?sequence=1&isAllowed=y ER -